Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.5.1.1 (asparaginase)
2,695 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The development of microbial enzymes for cancer therapy presents difficulties not commonly experienced with biological drugs. The development of the enzyme asparaginase from Escherichia coli in the USA and of the serologically different asparaginase from the plant pathogen Erwinia carotovora in this Establishment, has not only added to the choice of antileukaemia drugs but also provided a valuable guide to the selection and development of new therapeutic enzymes. Our own programme has led to the study of enzymes that degrade other amino acids (glutamine, arginine, phenylalanine and tyrosine) that appear to be important to certain leukaemia cells. Microbes with only remote associations with man were considered as a source of these to minimize initial immunological sensitivity. In the case of erwinia asparaginase the benefits of this have probably included a lower incidence of anaphylaxis compared with the escherichia enzyme. The selection of a stable, high-affinity enzyme that operates efficiently under physiological conditions ensures effective depletion of a circulating amino acid but the choice is very limited. It is also difficult to assess from laboratory tests the likely persistence, toxicity and efficacy of the enzyme in clinical use and to arrive at meaningful biological tests for the quality control of the finished product. Some of the difficulties will be described and proposals made for criteria of acceptance for this type of drug in experimental use.
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PMID:Amino acid degrading enzymes for cancer therapy. 41 22

A retrospective study was undertaken comparing the frequency and severity of anaphylactic reactions to E. coli-derived and Erwinia-derived asparaginase given intravenously on a weekly dosage schedule. Both drugs were found to produce life-threatening hypersensivity reactions with the chance of reaction per dose administered being almost identical--8% for each dose administered. Eleven of 31 patients (35%) experienced anaphylactic reactions, 9/27 (33%) with E. coli and 3/10 (30%) with Erwinia asparaginase, with one patient suffering anaphylaxis to both preparations. A marked increase in the percentage of patients having reactions occurred after the fourth dose of either preparation, with the incidence per dose increasing from 3.3% with the first dose to 32% on the fifth and subsequent doses. Rationale for an antibody-mediated allergic reaction is presented to explain the data.
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PMID:Comparison of anaphylactic reactions to asparaginase derived from Escherichia coli and from Erwinia cultures. 79 76

Management of E.-coli L-asparaginase induced anaphylaxis mainly consists of application of i.v. epinephrine but also in the withdrawal of this drug. Despite of this firm recommendation we have shown in 7 patients with E. coli L-asparaginase induced anaphylaxis, that further application of the drug is possible in the presence of a continuous epinephrine infusion (0.01-0.02 mg/kg) started one hour before and finished one hour after the concomittant infusion of the E.-coli L-asparaginase. In none of the patients there was a second event of anaphylaxis even though most of the patients still had to continue on E.-coli L-asparaginase with an average of more than 6 infusion.
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PMID:[Clinical experiences with adrenaline as therapy and prevention of E. coli-L-asparaginase-induced anaphylaxis]. 151 64

By using a modification of the microtiter solid-phase radioimmunoassay, we have measured Escherichia coli L-asparaginase (L-ASP) specific IgG, IgG4, and IgE antibodies in children who received L-ASP as part of their chemotherapy for leukemia and lymphoma. In 13 children with acute lymphoblastic leukemia induced with vincristine, prednisone, and L-ASP (10,000 IU/M2 i.v. each week for 3 weeks), seven developed high titer specific IgG antibodies. Four of the seven relapsed at the time of their peaking IgG response (6-10 months). None of the six with low or absent L-ASP antibody response have relapsed (followed for 20-35 months). In six children with allergic reactions to L-ASP reinduction, all had high titers of L-ASP specific IgG4 (greater than or equal to 20 U/ml) at the time of their reaction. In 16 other children with low L-ASP IgG4 (less than 13 U/ml), none demonstrated allergic reactions to rechallenge. Specific IgE was not consistently detectable in either group. In 21 patients with leukemia or lymphoma on L-ASP with cyclophosphamide-containing regimens, none developed significant IgG antibody response, compared with seven of 13 not receiving cyclophosphamide (p less than 0.001). We conclude: (a) development of L-ASP antibodies may have prognostic significance; (b) the detection of specific IgG4 can predict L-ASP allergy; and (c) cyclophosphamide-containing regimens reduce antibody formation to L-ASP and may allow repetitive (without anaphylaxis) and more effective (avoiding neutralizing antibodies) use of L-ASP.
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PMID:Antibody response to Escherichia coli L-asparaginase. Prognostic significance and clinical utility of antibody measurement. 352 39

Autologous red blood cells were loaded with L-asparaginase and injected intravenously into monkeys. A single dose of 1850 IU/Kg suppressed plasma asparagine for 19 days compared to 10 days for the same dose injected free in solution. Rabbit antisera to asparaginase was used to passively immunize guinea-pigs. These animals were then challenged with RBC-entrapped asparaginase versus asparaginase free in solution. RBC entrapment allowed a ten fold greater dose of asparaginase before anaphylaxis became a problem. RBC entrapment prolongs the duration of action of asparaginase and offers protection against anaphylaxis. Clinical trial in patients with acute lymphoblastic leukemia is recommended.
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PMID:Entrapment of L-asparaginase in red blood cells. A strategy to improve treatment of acute lymphoblastic leukemia. 400 65

In a series of 40 patients treated with L-asparaginase for various neoplastic diseases, 6 patients had generalized anaphylactic reactions to L-asparaginase. Each of these reactors had antibodies detectable by passive hemagglutination, but precipitins were detectable in only one of this group of six patients. That patient had received two courses of the enzyme. 1 wk after the anaphylactic reaction, complement-fixing antibodies were present in all the patients that were studied. Specific reagin antibodies (IgE) were demonstrated in one patient by the release of histamine from his leukocytes after incubation in vitro with L-asparaginase. Binding of L-asparaginase to serum antibodies after incubation in vitro was detected by selective precipitation of the complexes with 30% ammonium sulfate or by ultracentrifugation. Total inactivation of the enzyme did not occur even at optimal proportions or at antibody excess. Passive hemagglutinating antibodies to L-asparaginase were present in all patients who had an allergic reaction at least 1 day before the reaction occurred, when that sample was available, and were absent in all patients who did not manifest clinical allergy. Titration of antibodies by passive hemagglutination may thus provide a means of predicting impending anaphylaxis in this system, particularly when coupled with a sudden decrease in circulating levels of L-asparaginase activity.
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PMID:Immunological responses to L-asparaginase. 410 90

One hundred and ninety-one cases of acute lymphoblastic leukaemia were entered in a trial in which, for five months, all received cytotoxic therapy with prednisolone, vincristine, mercaptopurine, L-asparaginase, and methotrexate (the latter in high dosage followed by folinic acid). Patients were then randomized to receive immunotherapy (B.C.G.), twice-weekly methotrexate, or no further treatment.One hundred and seventy-seven patients (93%) achieved full remission and at the time of analysis, 26 months from the beginning of the trial, 143 were still alive, including 70 in their first remission. Median "post-intensive" remission lengths were 17 weeks (no treatment), 27 weeks (B.C.G.), and 52 weeks (methotrexate). The prolongation of remission by methotrexate was most evident in those patients with low initial white cell counts. B.C.G. seemed to cause lymphocytosis but was without other conspicuous effect. The incidence of toxic reactions is reported, including an unusually low rate of anaphylaxis with L-asparaginase.These preliminary results are discussed and compared with those of similar trials.
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PMID:Treatment of acute lymphoblastic leukaemia. Comparison of immunotherapy (B.C.G.), intermittent methotrexate, and no therapy after a five-month intensive cytotoxic regimen ((Concord trial). Preliminary report to the Medical Research Council by the Leukaemia Committee and the Working Party on Leukaemia in Childhood. 494 Jan 57

In order to evaluate enzyme loading of RBCs as a drug delivery system, the antitumor agent asparaginase was loaded into the erythrocytes of nine monkeys at three different doses and autologously injected back into these animals. Nine control monkeys were also once injected intravenously at the same doses of enzyme, but the enzyme was free in solution rather than entrapped in RBCs. The RBCs and asparaginase were labeled with 51Cr and 125I, respectively. The circulating half-life of the enzyme-loaded, resealed RBCs was 7 days, as compared to 9 days in the control RBCs. Beginning at 5 days, circulating enzyme activity was several orders of magnitude higher in the monkeys injected with RBC-loaded asparaginase than in controls. Targeting of drug-loaded RBCs into the spleen and liver was apparent. Suppression of the serum substrate level of asparaginase in the monkeys treated with the single intravenous injection of RBCs loaded with asparaginase was 20 days, which was twice as long as the suppression in the control monkeys. Production of anti-asparaginase antibody was shown to reach a higher level and persist longer in the monkeys with RBC-entrapped asparaginase. Evidence was also obtained showing that entrapping asparaginase in RBCs protects against anaphylaxis in the guinea pig. Thus this drug delivery system is also proposed as a strategy to avoid life-threatening allergic reactions. Advantages and limitations of RBC loading as a drug delivery system are discussed.
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PMID:Infusion of red blood cell-loaded asparaginase in monkey. Immunologic, metabolic, and toxicologic consequences. 618 74

L-asparaginase, a highly effective anti-leukemic enzyme preparation is now frequently being administered intramuscularly in order to decrease the incidence of severe sensitivity reactions. Although the occurrence of immediate hypersensitivity reactions and anaphylaxis has been diminished through this technique, we report three patients who developed delayed allergic reactions occurring hours after drug administration. This suggests that patients receiving L-asparaginase intramuscularly merit prolonged observation periods beyond the usual one half to one hour.
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PMID:Delayed allergic reactions following intramuscular L-asparaginase. 693 63

Hypersensitivity reactions from cytotoxic agents have not been accorded much attention. Certain drugs (L-asparaginase, cisplatin, intravenous melphalan, topical mechlorethamine, zinostatin, and teniposide) produce reactions often enough to be a clinical problem. Others (cyclophosphamide, doxorubicin, daunorubicin, methotrexate, and procarbazine) do so only occasionally. Bleomycin uniquely produces an occasional hyperpyrexic reaction with clinical findings similar to anaphylaxis. Some cytotoxic agents have never been known to produce hypersensitivity reactions. This paper reviews the frequency and clinical information about such reactions, factors augmenting or decreasing the frequency, and, where possible, the etiologic mechanisms.
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PMID:Hypersensitivity reactions to cancer chemotherapeutic agents. 700 2


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